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(Journal of Leukocyte Biology. 2001;69:907-911.)
© 2001 by Society for Leukocyte Biology

Control of chromatin accessibility for V(D)J recombination by interleukin-7

Jiaqiang Huang and Kathrin Muegge

Laboratory of Molecular Immuneregulation, SAIC-FCRDC, National Cancer Institute, Frederick, Maryland

Correspondence: Kathrin Muegge, SAIC-FCRDC, Laboratory of Molecular Immunoregulation, National Cancer Institute, Bldg. 560, Rm. 31-45, Frederick, MD 21702-1201. E-mail: MACROBUTTON HtmlResAnchor muegge{at}mail.ncifcrf.gov


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ABSTRACT
 
IL-7 is a key factor for lymphoid development, and it contributes to V(D)J recombination at multiple loci in immune-receptor genes. IL-7 signal transduction, involving {gamma}c and Jak3, is required for successful recombination at the TCR-{gamma} locus. IL-7 signaling controls the initiation phase of V(D)J recombination by controlling access of the V(D)J recombinase to the locus. In the absence of IL-7, the TCR-{gamma} locus is methylated and packaged in a repressed form of chromatin consisting of hypoacetylated histones. IL-7 signaling likely increases the acetylation state of the nucleosomal core histones resulting in an "open" form of chromatin. This opening leads to a higher accessibility for the transcription machinery and increased accessibility of the Rag heterodimer that performs the cleavage of DNA.

Key Words: lymphoid development • TCR-{gamma} locus • immunoglobulin • transposon • Rag-1/Rag-2


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MECHANISM OF V(D)J RECOMBINATION
 
V(D)J recombination is a unique, lymphoid-specific mechanism that allows the creation of novel immune-receptor genes. During V(D)J recombination, gene segments encoding parts of the immune-receptor genes are cut, recombined, and newly assembled, resulting in the expression of diverse T-cell receptors (TCRs) or immunoglobulins (Igs; reviewed in [1 ]). It is hypothesized that these rearranging genes evolved from an ancient retrotransposon that integrated into the germ line (reviewed in [2 ]). The target sites for recognition of the transposition separated from the transposon and integrated next to exons of a receptor gene. Subsequent events of gene duplication and mutation created the vast germline repertoire as we know it today with multiple-variable, joining, and diversity elements encoding immune-receptor genes (Fig. 1 ).



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  		Figure 1. Map of the murine TCR-{gamma} locus. V indicates variable regions; J, joining; and C, constant region. The regulatory regions HsA, J promoter, and constant region enhancer have been identified previously and consist of potential STAT5-binding sites [3 4 5 ]. The graph gives a schematic but not proportional view of the locus.

The target sites for the ancient transposon are now known as recognition sequences. These are short, conserved motifs consisting of a heptamer and nonamer sequence, separated by 12 or 23 bp of spacer DNA and located adjacent to the coding segments (Fig. 1) . The ancient transposon evolved into the recombination activation genes, rag-1 and rag-2. The Rag-1/Rag-2 dimer recognizes the synapsis formed by the 12mer and 23mer recognition motifs and initiates the cleavage step of V(D)J recombination. The resolution, processing, and ligation of the chromosomal ends involve many common DNA-repair enzymes such as Ku, DNA-PK, and XRCC4, which are not specific for V(D)J recombination but are also required for other processes involving the repair of double-strand DNA breaks (reviewed in [1 ]).

Two mechanisms guarantee the unlimited diversity of our immunoreceptor gene repertoire: the recombination event and the modification of the broken DNA ends before ligation. Taming the ancient transposon led to the creation of the unique process of V(D)J recombination, enabling us to encounter the antigenic diversity of our environment.


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CONTROL OF V(D)J RECOMBINATION IS REQUIRED FOR LYMPHOID DEVELOPMENT
 
The process of V(D)J recombination is an essential step for early lymphoid development. Without recombination and expression of the TCR or Igs, lymphocytes are blocked in development. Thus, a failure to recombine leads to severe immunodeficiency and ultimately, death of the organism. Conversely, an aberrant recombination event may result in chromosomal translocations and cancer development. Thus, control of V(D)J recombination is absolutely crucial for survival of the organism.

One level of control lies in rag gene expression (reviewed in [6 ]). Another level of control was first postulated by Alt and colleagues (reviewed in [7 ]) to explain cell-type specificity, time specificity, and locus specificity of V(D)J recombination. For example, T and B cells express rag-1 and rag-2 genes and share the same recognition sequences positioned adjacent to their immune-receptor genes. However, only T cells rearrange their TCR genes, and B cells, their Ig genes, fully. Thus cell-type specific changes are thought to regulate access for the Rag dimer to the TCR or Ig loci.

Thus, this raises the question as to the identity of the signals that control the process of V(D)J recombination and the molecular mechanism that regulates accessibility for Rag-mediated cleavage at a specific locus.


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INTERLEUKIN (IL)-7 SIGNALING IS REQUIRED FOR NORMAL LYMPHOID DEVELOPMENT
 
Earlier studies many years ago connected IL-7 and V(D)J recombination based on in vitro studies. IL-7 had been cloned over a decade ago by Namen and colleagues [8 ] as a pre-B-cell growth factor and subsequently had been demonstrated to affect the growth of T-cell precursors in vitro [9 ]. To understand the regulatory mechanism of V(D)J recombination, our laboratory studied TCR-gene rearrangement in lymphoid-precursor populations. We found that fetal-thymic organ cultures were able to undergo V(D)J recombination in vitro but not in fetal-thymic cell suspensions. V(D)J recombination could be associated with IL-7 expression in the thymic-organ culture, in contrast to the failure to detect IL-7 in thymic-suspension cultures. Addition of recombinant IL-7 to suspension cultures restored V(D)J recombination in vitro [10 ]. Furthermore, it was shown that fetal-liver cell suspensions or bone marrow-derived precursor T-cell populations that were cultured with recombinant IL-7 also undergo V(D)J recombination in vitro [11 12 13 ]. The ability of thymic-stromal cells to induce TCR rearrangement in lymphoid-precursor cells has been shown to be dependent on IL-7 gene expression itself [14 ]. Other studies demonstrated rag gene expression to be dependent on IL-7 [15 16 17 ].

IL-7 is expressed primarily in thymic, epithelial cells or bone marrow, stromal cells, the sites were T and B development, and V(D)J recombination occurs. Therefore, the in vitro studies suggested IL-7 as a candidate for regulation of this important step in early lymphoid development.

It is now well established that IL-7 plays a key role in lymphoid development. Mice that are deficient in the IL-7R{alpha} chain, first demonstrated by Peschon and colleagues [18 ], show a severe block in lymphoid development. T-cell precursors in the thymus of IL-7R{alpha}-/- mice arrest at the earliest stage of T-cell development (CD4-CD8-CD44+CD25-). At this early, T1 stage, V(D)J recombination is initiated usually, as we have shown previously [19 ]. Also, deletion of IL-7 itself or other components of the IL-7 signal-transduction pathway (such as {gamma}c and Jak3) leads to severe immune deficiencies in mice [20 21 22 23 24 ]. That IL-7 signal transduction is also important in humans was first demonstrated by Leonard and colleagues [25 ], identifying mutations in the {gamma}c chain as the cause of X-linked, severe combined immunodeficiency (SCID) in humans. Later, mutations in Jak3 gene or aberrant regulations of the IL-7R{alpha} chain have been shown to be responsible for human immune deficiencies (reviewed in [26 ]). Thus, IL-7 is crucial for lymphoid development in mice or men.

However, the effects of IL-7 in vivo are complex and at least partially trophic (i.e., IL-7 affects the survival of lymphoid precursor cells) and partially based on a direct effect on the process of V(D)J recombination itself (reviewed in [27 , 28 ]). Consequently, immune deficiencies as they occur in IL-7R{alpha}-deficient mice can be restored partially by introduction of a bcl-2 transgene (substituting for the trophic requirement of IL-7) or are restored partially by introduction of a rearranged TCR transgene [17 , 29 ].

We and others have addressed the question of how IL-7 affects V(D)J recombination in vivo and have demonstrated that IL-7 alters accessibility for the V(D)J recombinase specifically.


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IL-7 IS REQUIRED FOR TCR-{gamma} GENE REARRANGEMENT
 
What is the evidence that IL-7 plays a role in the regulation of V(D)J recombinaton in vivo? Ikuta and colleagues [30 ] and work by our laboratory [19 , 31 , 32 ] (Table 1 ) established that mice that are deficient in the IL-7R{alpha} chain show a severe deficiency of gene rearrangement at the three productive TCR-{gamma} loci. This defect is truly dependent on IL-7 itself and not on TSLP, another stromal, cell-derived cytokine [33 ]. Although TSLP and IL-7 share the IL-7R{alpha} chain, the {gamma}c chain and Jak3 are unique to the IL-7 signal-transduction pathway [34 ]. Mice that are deficient in the latter two signal-transduction components, as we have shown, also lack TCR-{gamma} chain rearrangement [32 ]. The suppression of TCR-{gamma} rearrangement is not the only recombination defect as a result of the absence of IL-7 signaling: IL-7R{alpha}-/- mice fail to recombine their Ig heavy-chain locus efficiently [35 ], and IL-7-/- mice show a delayed onset in TCR-ß chain rearrangement [36 ]. Thus, multiple sites are affected in their capacity to recombine in the absence of IL-7 signaling.


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  		Table 1. Effect of IL-7 on V(D)J Recombination

The defect in TCR{gamma} chain rearrangement could explain the lack of TCR-{gamma}{delta} T cells in IL-7R{alpha}-/- mice because successful recombination is a prerequisite for T-cell survival and development. Alternatively, an inhibition of {gamma}{delta} T-cell development could be the reason for undetectable TCR-{gamma} rearrangement. The following findings argue against this second possibility: T1 cells, in the earliest stage of thymic, T-cell development and the stage at which IL-7R{alpha}-/- thymocytes are arrested, initiate rearrangement at the TCR-{gamma} and -ß loci at the same time, as we demonstrated recently [19 ]. As a result, most {alpha}ß T cells have a rearranged TCR-{gamma} locus. Furthermore, mice that lack any {gamma}{delta} T cells as a result of a deletion of the TCR-{delta} chain, show normal levels of TCR-{gamma} chain rearrangement [31 ]. Thus, the lack of TCR-{gamma} rearrangement in IL-7R{alpha}-/- mice is not lineage-dependent but is a result of a defect in recombination. In further support, IL-7R{alpha}-deficient mice that are bred onto the C57BL/6J strain are leaky in {alpha}ß T-cell development. However, we could demonstrate that these mice have no detectable TCR-{gamma} chain rearrangement, although the requirement for IL-7 to promote pro-T-cell survival is less stringent on the C57 background [19 ]. Finally, Ikuta and colleagues [3 ] have demonstrated that IL-7R{alpha}-/- mice expressing a bcl-2 transgene also show no evidence of TCR-{gamma} chain rearrangement (Table 1). These results indicate that the lack of TCR-{gamma} rearrangement in the absence of IL-7 signaling is because of an effect on V(D)J recombination and not secondary to an effect on survival.


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IL-7 CONTROLS INITIATION OF Rag-MEDIATED CLEAVAGE
 
The absence of V(D)J recombination at the TCR-{gamma} locus was demonstrated first by a failure to detect completed, ligated, recombination products by Southern or polymerase chain reaction (PCR) analysis. These techniques do not determine which step of V(D)J recombination was inhibited in the absence of IL-7 signaling: the initiation of cleavage or the processing and ligation of the chromosomal ends. This latter possibility had been demonstrated recently to occur as a consequence of deletion of the TCR-ß enhancer in mice [37 ]. Thus, we searched for the presence of recombination intermediates in IL-7R{alpha}-/- thymocytes using ligation-mediated PCR analysis that allows for detection of broken DNA ends. The failure to detect any recombination intermediates indicated that IL-7R{alpha}-deficient mice do not initiate cleavage at the TCR-{gamma} locus [32 ]. This result suggests that IL-7 signaling leads to an alteration of accessibility for Rag-mediated cleavage at the locus rather than controlling subsequent steps of recombination such as ligation. In support of this interpretation, we also found a reduction in germ-line transcripts at the TCR-{gamma} locus [32 ]. Similarly, a lack of Ig heavy-chain, germ-line transcripts has been shown in IL-7R{alpha}-/- mice [35 ]. Germ-line transcripts are correlated closely with the recombination event. Usually, they precede rearrangement briefly and are thought to indicate an open-chromatin state.

To test directly whether IL-7 controls chromatin accessibility, we used the Rag-mediated cleavage assay developed by Schlissel and colleagues [38 ]. Originally, their work established that cell-type specificity of V(D)J recombination is dependent on alteration of target-site accessibility. Nuclei derived from IL-7R{alpha}-/- thymocytes were exposed to recombinant or purified Rag proteins in vitro, and the chromatin was tested for the initiation of the cleavage reaction. Thymocytes of IL-7R{alpha}-deficient mice show a suppression of recombination intermediates, indicating a reduced access of Rag proteins [19 ]. These results establish that IL-7 signaling controls chromatin accessibility for Rag-mediated cleavage at the TCR-gg locus.


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IL-7 CONTROLS CHROMATIN ACCESSIBILITY FOR V(D)J RECOMBINATION
 
How does IL-7 regulate chromatin accessibility specifically? To test for the presence of repressed chromatin in the absence of IL-7, first we examined the methylation status of the TCR-{gamma} locus. DNA methylation is associated closely with heterochromatin, a nontranscribed form of chromatin. Using restriction enzymes that are sensitive to DNA methylation, we have demonstrated by Southern analysis that the TCR-{gamma} locus is methylated in the absence of the IL-7 signal [32 ]. Similarly, it was shown recently that the TCR-ß locus is methylated in mice with a deletion of the constant region enhancer, a region that is required for successful V(D)J recombination [39 ]. Furthermore, methylation of recombination plasmid substrates [40 ] or episomal substrates [41 ] inhibits the efficiency of V(D)J recombination. Thus, DNA methylation is associated with inhibition of V(D)J recombination.

How does methylation of the TCR-{gamma} locus lead to a suppressed form of chromatin, and how can IL-7 signaling overcome this suppression? Bird and colleagues [42 ] revealed part of the mechanism by which DNA methylation results in repressed chromatin and a reduction in the transcriptional process. They demonstrated that methylated DNA binds to methyl-DNA-binding proteins, such as MecP2, which then associates with histone acetylases rendering histones unacetylated. The unacetylated nucleosomes, formed by the histone core, are associated with a transcriptionally suppressed form of chromatin. Addition of a specific, histone-deacetylase inhibitor, such as Trichostatin A (TSA), can de-repress transcription by elevation of histone-acetylation levels. Thus, TSA can overcome the suppression of transcription caused by methylation.

We were able to circumvent the need for IL-7 signaling in V(D)J recombination by TSA. Thymocytes from IL-7R{alpha}-/- mice cultured in the presence of an increasing dose of TSA were able to recombine successfully at their TCR-{gamma} locus [32 ]. Similarly, it was shown recently that TSA can overcome the suppression of TCR-ß recombination caused by deletion of the ß constant region enhancer [39 ], or V{kappa} rearrangement can be induced in a pre-B-cell line [43 ]. Furthermore, a block of V(D)J recombination caused by deletion of regulatory sequences in the TCR-ß or -{delta} genes correlates with low levels of histone-3 acetylation at the specific loci [39 , 44 ]. These findings suggest that histone acetylation is an important prerequisite for accessible chromatin, and IL-7 can modulate histone acetylation specifically at the TCR-{gamma} locus for V(D)J recombination.


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CONCLUSION AND UNRESOLVED QUESTIONS
 
IL-7 signaling is required for normal lymphoid development, and part of its effect in vivo is the control of V(D)J recombination at the TCR-{gamma} locus. Based on the findings of our laboratory and others, we derive the following model for the molecular mechanism of IL-7 effects (Table 1) : IL-7 signaling leads to activation of specific transcription factors binding to regulatory sequences in the TCR-{gamma} locus (Fig. 1) . These regulatory sites may include recently identified transcriptional-response elements such as the constant-region enhancer, the J-{gamma} promoter, or the human serum albumin (HSA) binding site located between the variable regions [3 4 5 ]. The binding leads to recruitment of associated histone acetylases at the TCR-{gamma} locus. Specific histone acetylation will lead to an "accessible" form of chromatin correlating with unmethylated DNA and possibly leading to further modifications of chromatin including repositioning of nucleosomes and disruption of higher-order chromatin structure. This opening of chromatin will allow access of the transcriptional machinery and the appearance of sterile transcripts. The open form of chromatin will also permit access of the Rag dimer forming recognition synapsis and initiating the first step of V(D)J recombination, the site-specific cleavage.

The effect of histone acetylation on altering access for the Rag dimer is still unresolved. It has been shown that the core histones in the nucleosome are inhibitory for Rag-mediated cleavage in vitro [45 , 46 ]. However, acetylation of the N-termini of the histones does not relieve this repression in vitro [43 , 45 ]. Thus, histone acetylation may rather affect higher-order chromatin structure in vivo. It is also possible that the histone acetylation in vitro does not mimic the complex acetylation pattern in vivo (involving at least eight different lysine residues at histone 3 or 4) or that other histone modifications such as phosphorylation, methylation, or poly-adenosine 5'-diphosphate (ADP)-ribosylation also contribute to modulation of Rag accessibility. Another possibility is that histone-acetylated N-termini of the histones serve as flags to attract SNF/complexes. Those large SNF complexes can disrupt nucleosomal arrays in vitro and cause sliding of nucleosomes along DNA, thus allowing increased access of other DNA-binding factors. These and other possibilities require future studies.

Currently, it is not known how the IL-7 signal transmits from the membrane to the nucleus and how a histone acetylase is targeted specifically to the TCR-{gamma} locus. The transcription factor Stat5, translocating to the nucleus in response to IL-7, is a candidate gene for specific IL-7 signal transduction. Stat5 is not activated in IL-7R-/- thymi or pre-B cells. Stat5 can complex via the Nmi adaptor protein with the histone acetylase CBP/p300 [47 ]. Furthermore, Stat5 has been shown to bind to the J-{gamma} promoter, and there are several other potential Stat5 binding sites in the TCR-{gamma} locus [3 ]. Thus, Stat5 would be a good candidate to target histone-acetylase activity, specifically to the TCR-{gamma} locus. In support of this model, Ikuta and colleagues [3 ] have demonstrated recently that Stat5 can substitute for IL-7 signaling, because a Stat5 transgene can restore TCR-{gamma}-chain rearrangement in IL-7R{alpha}-/- mice. However, mice that are deficient in Stat5a and b have been shown to have normal lymphoid development [48 , 49 ]. This argues against Stat5 (although able to substitute for IL-7 signaling), serving as a mediator for histone acetylation in vivo.

Revealing the molecular mechanism whereby IL-7 controls accessibility specifically for V(D)J recombination at the TCR-{gamma} locus may ultimately provide insights to many cytokine-regulated processes involving alteration of chromatin structure.


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ACKNOWLEDGEMENTS
 
This project has been funded in whole or part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-56000. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank Drs. Scott Durum and Joost Oppenheim for critical review of the manuscript.

Received December 13, 2000; accepted January 19, 2001.


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